(a) Field of the Invention
The invention relates to novel 6-heterocyclyl-pyrazolo [3,4-d]-pyrimidin-4-ones, which inhibit the enzymatic activity of phosphodiesterase (PDE), and to the preparation thereof and the use thereof in treating cardiovascular disease.
(b) Information Disclosure Statement
U.S. Pat. No. 3,165,520 to Schmidt et al. discloses as coronary dilating agents pyrazolo[3,4-d]pyrimidines of general formula: ##STR1## wherein: R.sup.1 represents a hydrogen atom or an alkyl, hydroxyalkyl, halogen-alkyl or oxa-alkyl radical or a cycloalkyl, cycloalkylalkyl, aralkyl or heterocyclylalkyl radical or an at most binuclear aryl or heterocyclic radical;
R.sup.3 represents a hydrogen atom or a lower-alkyl radical; PA1 R.sup.5 represents an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, araliphatic or heterocyclic-aliphatic radical; and PA1 R.sup.6 represents an aliphatic radical or an aralkyl or heterocyclyl-alkyl radical which may be substituted. PA1 R.sup.3 stands for hydrogen, or in the second place, for a lower-alkyl radical; and PA1 R.sup.6 represents a possibly substituted aralkyl or heterocyclylalkyl radical. PA1 The patent more specifically discloses as especially valuable the compounds in which R.sup.1 represents a hydrogen atom or a lower-alkyl group; R.sup.3 represents a hydrogen atom or lower-alkyl and R.sup.6 an aralkyl. PA1 R.sup.1 represents a hydrogen atom, a lower-alkyl radical which is unsubstituted or substituted by a hydroxy group or a lower-alkoxy group, or a cyclopentyl or cyclohexyl radical or a phenyl or phenyl lower-alkyl radical; PA1 R.sup.3 represents a hydrogen atom or a lower-alkyl radical; and PA1 R.sup.6 stands for a phenyl lower-alkyl radical or a phenyl radical which may be substituted. PA1 n is 0-4; and PA1 Ar is: ##STR6## or 2, 3 or 4-pyridyl wherein X, Y and Z are independently (1) hydrogen; (2) lower-alkyl of from one to six carbons, inclusive; (3) halogen; (4) hydroxyl; (5) lower-alkoxy of from one to six carbons, inclusive; (6) nitro; (7) amino; (8) NR'R" wherein R' and R" are each independently (a) hydrogen or (b) lower-alkyl of from one to six carbons, inclusive, optionally substituted by (i) amino, (ii) morpholino, or (iii) cycloalkyl of from five to seven carbons, inclusive, (9) sulfonyl or (10) --SO2 NR'R" wherein R' and R" are as defined above. PA1 R.sup.3 is hydrogen, lower-alkyl, phenyl-lower-alkyl, lower-alkoxyphenyl-lower-alkyl, dilower-alkoxyphenyl-lower-alkyl, pyridyl-lower-alkyl, cycloalkyl-lower-alkyl, phenylamino, dialkylamino, halogen, trifluoromethyl, lower-alkylthio, cyano or nitro; and PA1 R.sup.6 is a five or six membered heterocyclic ring containing from one to two nitrogen atoms, or a nine or ten membered bicylic ring containing from one to two nitrogen atoms, or any of these substituted at any available carbon atom by one or two substituents, the same or different, selected from the group consisting of lower-alkyl, halogen, lower-alkoxy, cycloalkyloxy, 4-morpholinyl, lower-alkoxy-lower-alkoxy, hydroxy, imidazolyl, oxo and 4-morpholinyl-lower-alkoxy; or at any available nitrogen atom by lower-alkyl, lower-alkanoyl, or trifluoroacetyl; or a pharmaceutically acceptable acid-addition salt thereof. PA1 R.sup.6 is pyridyl, or pyridyl substituted by one or two substituents, the same or different, selected from the group consisting of lower-alkyl, halogen, lower-alkoxy, cycloalkyloxy, lower-alkoxy-lower-alkoxy, imidazolyl, and 4-morpholinyl-lower-alkoxy; PA1 R.sup.1 is alkyl, cycloalkyl or substituted phenyl-lower-alkyl; and PA1 R.sup.3 is lower-alkyl, trifluoromethyl, phenyl-lower-alkyl, dilower-alkoxyphenyl-lower-alkyl, pyridyl-lower-alkyl or cycloalkyl-lower-alkyl. PA1 R.sup.6 is 4-pyridyl, or 4-pyridyl substituted by one or two substituents, the same or different, selected from the group consisting of lower-alkyl, halogen, lower-alkoxy, cycloalkyloxy, lower-alkoxy-lower-alkoxy, imidazolyl, and 4-morpholinyl-lower-alkoxy; PA1 R.sup.1 is tert-butyl or cyclopentyl; and PA1 R.sup.3 is lower-alkyl, trifluoromethyl, phenyl-lower-alkyl, dilower-alkoxyphenyl-lower-alkyl, pyridyl-lower-alkyl, or cyclo-alkyl-lower-alkyl.
The patent more specifically discloses as especially valuable the compounds in which R.sup.1 represents a hydrogen atom or a lower-alkyl radical; R.sup.3 represents a hydrogen atom or a lower-alkyl radical; R.sup.5 represents a lower-alkyl radical and R.sup.6 represents a lower-alkyl radical or an aralkyl radical.
U.S. Pat. No. 3,211,731 to Schmidt et al. discloses as coronary dilating agents pyrazolo[3,4-d]pyrimidines of general formula: ##STR2## wherein: R.sup.1 represents hydrogen, an alkyl, hydroxy-alkyl, halogen-alkyl or oxa-alkyl radical, a cyclo-alkyl, cycloalkylalkyl, aralkyl, heterocyclyl-alkyl radical or an at most binuclear aryl or heterocyclic radical;
U.S. Pat. No. 3,211,732 to Schmidt et al. discloses as intermediates 1-R.sup.1 -3-R.sup.3 -6-R.sup.6 -4-hydroxy-pyrazolo [3,4-d]pyrimidines wherein:
U.S. Pat. No. 3,732,225 to Breuer et al. discloses as hypoglycemic agents and anti-inflammatory agents pyrazolo[3,4-d]-pyrimidines of formula: ##STR3## wherein: R is hydrogen or lower-alkyl; R.sup.1 is lower-alkyl, cycloalkyl, phenyl or substituted phenyl; R.sup.2 is phenyl, substituted phenyl or cycloalkyl; and R.sup.3 is hydrogen, lower-alkyl, cycloalkyl, phenyl or substituted phenyl.
U.S. Pat. No. 3,350,397 to Burch discloses as antibacterial agents pyrazolo[3,4-d]pyrimidines of formula: ##STR4## wherein: R represents a member of the group consisting of hydroxy, chloro and --n(X)(Y) wherein X represents a member of the group consisting of hydrogen, (lower) alkyl, hydroxy (lower) alkyl, (lower)alkoxy(lower)alkyl and amino; Y represents a member of the group consisting of hydrogen, hydroxy (lower) alkyl, (lower) alkoxy(lower)alkyl and morpholinopropyl; X and Y taken together with N represent pyrrolidyl; and R.sup.1 represents a member of the group consisting of (lower)alkyl and methoxyethyl.
The patent further discloses, as intermediates, 4-amino and 4-hydroxy-1-R.sup.1 -6-(2-furyl)-1H-pyrazolo [3,4-d]pyrimidines. The preparation of intermediates and the preparation and biological testing of final products is further exemplified by Burch in J. Med. Chem. 1968, 11, 79.
British Patent 937,722 to CIBA LIMITED discloses as a coronary dilating agent 1-isopropyl-4-hydroxy-6-benzyl-pyrazolo[3,4-d]pyrimidine.
U.S. Pat. No. 4,666,908 to Hamilton discloses pyrazolo [4,3-d]pyrimidine-7-ones of formula: ##STR5## wherein: R.sup.1 is lower-alkyl of from one to six carbons, inclusive, lower-alkylene of from one to six carbon, inclusive, lower-hydroxyalkyl of from one to six carbons, inclusive, lower-hydroxyalkylene of from two to six carbons, inclusive, lower-aminoalkyl of from one to six carbons, inclusive, or lower-aminoalkylene of from two to six carbons, inclusive;
The patent more specifically discloses as preferred compounds those wherein Ar is R.sub.2. The compounds are stated to be useful in the treatment of cardiovascular disorders.
Miyashita et al. (Heterocycles 1900, 31, 1309.) describes the preparation of a series of pyrazolo[3,4-d]pyrimidines of general formula: ##STR7## wherein: R is phenyl or methyl; and R.sup.1 is hydrogen, methyl, ethyl, propyl, isopropyl, benzyl, ethyl carboxylate or phenyl. No indication of utility is disclosed.
Hamilton PCT Application WO 88/00192, published Jan. 14, 1988, discloses a series of 5-substituted pyrazolo [4,3-d]pyrimidin-7-one derivatives useful as cardiotonic, CNS stimulative, antiallergy, antiasthma or cognition activating agents.
Bell et al. European Patent Application 0463756, published Jan. 2, 1992, disclose a series of 5-(2,5-disubstituted-phenyl)pyrazolo[4,3-d]pyrimidin-7-ones useful in the treatment of cardiovascular disorders.